In 30 to 40% of acute hepatitis cases attendant on hepatitis C virus (HCV) infection, HCV will not be detectable in time, leading to the normalization of hepatic function, while in 60 to 70% thereof, patients with acute hepatitis become HCV carriers, that is to say, develop hepatitis C. The probability that hepatitis C goes into spontaneous remission is extremely low, 0.2%, and 10 to 16% of hepatitis C cases progress to cirrhosis 20 years on average after the primary infection. In cirrhosis cases, hepatocellular carcinoma occurs at a high annual rate of not less than 5%. It is inferred that, if patients with hepatitis C aged 40 years are left without any appropriate treatment until the age of 70, 20 to 25% of them develop hepatocellular carcinoma. The annual mortality of liver cancer is over 30,000 in total, and is still increasing, whereupon about 80% of the dead had hepatitis C (Non-Patent Document 1).
Under these circumstances, it is a national task to treat and cure hepatitis C, and the administration of interferon (IFN)-α alone or in combination with ribavirin is generally performed as a treatment for hepatitis C. It, however, is said that the HCV elimination rate is about 30% for IFN-α alone, and about 40% if IFN-α and ribavirin are administered in combination. A poorer effect of interferon therapy on hepatitis C is argued from two points of view. Specifically, there is a problem with the genotype of HCV. Hepatitis C may clear up after treatment merely in one per three patients with genotype 1 hepatitis C, and two per three patients with genotypes 2 and 3 hepatitides C (Non-Patent Literature 2).
Another problem dwells in hepatic steatosis. Hepatic steatosis in hepatitis C is different from that in simple fatty liver or hepatitis B in that C18:1 fatty acids, such as oleic acid (18:1(9)) and vaccenic acid (18:1(11)), are accumulated in larger amounts. HCV is considered to cause fatty liver specific to hepatitis C by affecting a particular pathway in the lipid metabolism (Non-Patent Literature 3).
In hepatitis C, the presence of hepatic steatosis weakens the therapeutic effect of an antiviral agent on hepatitis C. By a combined application of IFN-α and ribavirin, sustained virological response (SVR) was achieved in 66% of the patients not having hepatic steatosis, but in 50% on average of the patients having hepatic steatosis (Non-Patent Literature 4).
In hepatitis C in which hepatic steatosis is very likely to be observed, the therapeutic effect of an antiviral agent on hepatitis C is thus weakened if hepatic steatosis is present, which suggests that not only HCV elimination but some measures against hepatic steatosis are required in the treatment of hepatitis C.
Hepatic steatosis in hepatitis C and HCV core protein are involved in each other. The HCV core gene transgenic mice had such a hepatic lipid composition that C18:1 fatty acids were accumulated in larger amounts than in the mice having simple obesity. Similar difference in hepatic lipid composition was observed between fatty liver patients with HCV infection and those without HCV infection (Non-Patent Literature 3).
On the other hand, HCV core protein attaches to lipid droplets accumulated in the liver by the HCV core protein, and forms new HCV around the lipid droplets (Non-Patent Literature 5).
In other words, in hepatitis C, HCV core protein conducts lipid accumulation or steatosis in the liver through a unique process differing from the process of any other type of fatty liver, and lipids accumulated in the liver promote HCV proliferation. HCV proliferation and hepatic steatosis are exacerbation factors in each other, that is to say, there exists a cycle of hepatitis C exacerbation between HCV proliferation and hepatic steatosis. Nothing but the breakage of the cycle of hepatitis C exacerbation is necessary for the optimization of the treatment of hepatitis C.
Polyunsaturated fatty acids (PUFAs) are defined as those fatty acids each of which has a plurality of carbon-carbon double bonds in the molecule, and classified as ω-3 fatty acids, ω-6 fatty acids, and so forth in accordance with the positions of double bonds. Exemplary ω-3 polyunsaturated fatty acids (ω-3 PUFAs) include α-linolenic acid, icosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
It is reported that polyunsaturated fatty acids such as arachidonic acid, EPA and DHA inhibited HCV replication in a cell culture system using Ava5 cells (Non-Patent Literature 6).
It is also reported on the case of using OR6 cells that, out of linoleic acid, arachidonic acid, EPA and DHA, only linoleic acid had the HCV replication-inhibiting effect which is independent of cytotoxicity (Non-Patent Literature 7), so that it has been controversial whether EPA and DHA have the HCV replication-inhibiting effect on not.
There is a report on the administration of ω-3 PUFAs additional to interferon therapy in the treatment of hepatitis C. When the interferon administered group and the group to which interferon plus ω-3 PUFAs were administered were compared with each other, the serum HCV-RNA level was reduced in both groups significantly as compared with that before administration, and the degree of reduction did not differ significantly between the groups (Non-Patent Literature 8). In terms of hypertriglyceridemia occurring as a side effect of interferon therapy, it is reported in the same article that ω-3 PUFAs had an effect of ameliorating hypertriglyceridemia due to interferon therapy.
In addition, it is reported that EPA can prevent anaemia during combination therapy with interferon and ribavirin (Patent Literature 1).
The reports as above indicate that ω-3 PUFAs are effective at relieving various side effects of interferon therapy for hepatitis C. At the same time, they imply that administration of ω-3 PUFAs did not have direct effects on the treatment of hepatitis C in itself.